CN112375122A - Preparation method of dienogest and method for recovering dienogest from dienogest mother liquor - Google Patents
Preparation method of dienogest and method for recovering dienogest from dienogest mother liquor Download PDFInfo
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- AZFLJNIPTRTECV-FUMNGEBKSA-N dienogest Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)([C@](CC3)(O)CC#N)CC3)C3=C21 AZFLJNIPTRTECV-FUMNGEBKSA-N 0.000 title claims abstract description 67
- 229960003309 dienogest Drugs 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 25
- 239000012452 mother liquor Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000007787 solid Substances 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- OVRKATYHWPCGPZ-UHFFFAOYSA-N 4-methyloxane Chemical compound CC1CCOCC1 OVRKATYHWPCGPZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 abstract description 8
- 238000010511 deprotection reaction Methods 0.000 abstract description 7
- 239000003270 steroid hormone Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- 239000006227 byproduct Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- 229940126657 Compound 17 Drugs 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010030247 Oestrogen deficiency Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940008227 dienogest and estradiol Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960004766 estradiol valerate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000000757 progestagenic effect Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Toxicology (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of dienogest and a method for recovering dienogest from dienogest mother liquor, wherein the preparation method of dienogest comprises the steps of dissolving 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-diketone-3, 3-ethylidene ketal, adding fluoboric acid, carrying out acidolysis for deprotection, and carrying out treatment after complete reaction to obtain dienogest; the method for recovering dienogest from dienogest mother liquor comprises the steps of dissolving dienogest by using a solvent to obtain dienogest mother liquor, adding perchloric acid or concentrated hydrochloric acid, reacting for a period of time, heating to 45-55 ℃, concentrating under reduced pressure, stopping concentration when partial solvent is concentrated until solid is separated out, cooling, continuing to react, and treating after the reaction is finished to obtain dienogest.
Description
Technical Field
The invention belongs to the technical field of preparation of steroid hormone medicaments, and particularly relates to a preparation method of dienogest and a method for recovering dienogest from dienogest mother liquor.
Background
Dienogest (Dienogest) is a progestogenic drug with the chemical name 17 α -cyanomethyl-17 β -hydroxy-13 β -methylstane-4, 9-dien-3-one, which was marketed in germany as a contraceptive in 1995 (2mg +0.03mg) and in australia in 2007 under the name Valette. In 2001, a compound preparation of dienogest and estradiol valerate (containing 2mg of dienogest and 1 or 2mg of estradiol valerate) is marketed by mr. Ling company in Germany for hormone replacement therapy for women with estrogen deficiency for more than one year at menopause. It was marketed in 2002 in European countries such as Denmark, France, Belgium, etc. under the trade name Climodie. Dienogest tablets (1mg) were marketed in japan in 2007 for the treatment of endometriosis.
In recent years, the synthesis process of dienogest is as follows: androstane-4, 9-diene-3, 17-diketone is taken as an initial raw material, protected by a 3-keto group, reacted by acetonitrile and n-butyllithium at low temperature to form 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstane diene-3, 17-diketone-3, 3-ethylidene ketal, and finally subjected to acidolysis and deprotection to obtain a compound 17 alpha-cyanomethyl-17 beta-hydroxy-4, 9-diene-3 ketone. The final step of acid hydrolysis and deprotection is a key step, strong acids such as perchloric acid and sulfuric acid are generally adopted for acidolysis in the traditional method, but certain destructiveness is generated on a substrate when strong acids such as perchloric acid and sulfuric acid are adopted for acidolysis, the color of a generated crude product is dark yellow, and an obtained refined product is still yellow through a common refining method such as a decolorizing agent. Some companies adopt concentrated hydrochloric acid for acidolysis and deprotection to obtain crude products, the purity of the crude products is more than or equal to 98 percent after twice recrystallization by acetone, the yield is only 43.5 percent, and the yield is very low. In addition, the obtained crude product has the purity of 70 percent only by adopting acidolysis deprotection of p-toluenesulfonic acid, hydrochloric acid, acetic acid and the like, and the raw material medicament meeting the medicinal standard can be obtained only by 3-5 times of recrystallization.
Disclosure of Invention
The invention aims to provide a preparation method of dienogest and a method for recovering dienogest from dienogest mother liquor, and the product has high purity, high yield and good color.
The invention relates to a preparation method of dienogest, which comprises the steps of dissolving 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal, adding fluoboric acid (the fluoboric acid preferably exists in the form of a fluoboric acid aqueous solution with the mass concentration of 40-50 percent), carrying out acidolysis and deprotection, and treating after the reaction is completed (the reaction temperature is preferably 20-45 ℃ C.), thus obtaining the dienogest.
Preferably, the solvent in which 17 α -cyanomethyl-17 β -hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylene ketal is dissolved is methanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, acetone, or 4-methyl-tetrahydropyran, more preferably acetonitrile.
The treatment is generally to adjust the pH of the solution after the reaction to 7-8 by using a sodium carbonate solution, slowly pouring the reaction solution into water, stirring for elutriation, filtering, and drying a filter cake at 50-60 ℃ to obtain the dienogest.
The invention also provides a method for recovering dienogest from dienogest mother liquor, which comprises the steps of dissolving dienogest with a solvent to obtain dienogest mother liquor, adding perchloric acid or concentrated hydrochloric acid, reacting for a period of time, heating to 45-55 ℃, concentrating under reduced pressure, stopping concentrating when partial solvent is removed and solid is separated out, cooling, continuing to react, and treating after the reaction is finished to obtain dienogest.
The solvent of the concentrated dienogest mother liquor is methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile.
Perchloric acid exists in the form of perchloric acid aqueous solution, and the mass concentration is 70%; the mass concentration of the concentrated hydrochloric acid is 20-38%; more preferably perchloric acid.
The vacuum degree of the decompression concentration is-0.07 Mpa to-0.05 Mpa.
The dienogest is purified before dissolving it in a solvent, and the dienogest is purified by heating, refluxing and clearing the solvent (preferably dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, 4-methyl-tetrahydropyran, acetone, toluene, ethyl acetate or acetonitrile, more preferably 4-methyl-tetrahydropyran) for dienogest with activated carbon, filtering, and recrystallizing to obtain a refined dienogest.
The treatment method comprises the steps of adjusting the pH of the solution after the reaction to 7-8 by using a sodium carbonate solution, pouring the reaction solution into water, stirring for elutriation, filtering, and drying a filter cake to obtain the dienogest.
The beneficial effect of the invention is that,
at present, acid hydrolysis is generally carried out on acid substances such as perchloric acid, concentrated hydrochloric acid, dilute sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid or hydrogen chloride gas during preparation of dienogest, but by-products of the acid hydrolysis reaction are large, the product and the by-products are extremely similar in structure, physical properties such as molecular polarity and solubility are very close, and the by-products are refined into mother liquor during later refining, so that the yield is low. Meanwhile, the acidolysis product is dark yellow and is difficult to remove.
The inventor finds that the fluoroboric acid is used as a reagent for acidolysis reaction, the generation of other impurities can be well controlled, the purity and the yield of the fluoroboric acid are higher than those of acidolysis products of other acids, and in a comparative experiment, the acidolysis products of perchloric acid and concentrated hydrochloric acid are dark yellow in color, and more byproducts are generated than the acidolysis products of fluoroboric acid. The method takes the fluoboric acid as a reagent for acidolysis reaction, and the product is white-like, thereby effectively inhibiting the generation of by-products and improving the yield and the purity. More importantly, a solid foundation is laid for a later method for recovering dienogest from dienogest mother liquor.
17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal is subjected to acidolysis for deprotection to obtain a compound 17 alpha-cyanomethyl-17 beta-hydroxy-4, 9-diene-3 ketone, and an acetonitrile reaction system is subjected to water separation to obtain a crude product with the purity of more than 98% and the purity of a byproduct 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-diene-3 ketone of about 1%. The purity of the refined product is more than 99.5 percent, the yield is about 75 to 80 percent, the by-product 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-diene-3 ketone is about 4 to 5 percent, the by-product is completely enriched in the mother liquor, and the rest is the product. About 20% of the refined mother liquor is lost once, and if the refined mother liquor is treated by three wastes, unnecessary economic loss and waste can be caused, and the current yield is only about 40%.
The invention uses a strong acid to continuously treat the refined mother liquor once, and can completely convert the byproduct 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-diene-3 ketone into the target product 17 alpha-cyanomethyl-17 beta-hydroxy-4, 9-diene-3 ketone. And the product which meets the medicinal standard is obtained after recrystallization, the total yield is greatly improved, and the production cost of enterprises is reduced.
According to the invention, the qualified dienogest finished product is obtained after the refined mother liquor is treated and recovered, and the total yield is improved by 10-15% compared with that of the conventional method; and the generation of three wastes is reduced, unnecessary waste is reduced, and the economic benefit of enterprises is increased.
Drawings
FIG. 1 is a flow chart of the present invention for recovering dienogest.
FIG. 2 is a diagram showing the mechanism of the acidolysis reaction according to the present invention.
FIG. 3 is a reaction scheme of the present invention.
Detailed Description
Example 1
The method comprises the following steps: preparation of the indicated Compound B, 17 α -cyanomethyl-17 β -hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal
Adding 150ml of 2.5mol/L n-butyllithium into a reaction bottle, cooling to below-50 ℃, adding 300ml of tetrahydrofuran, continuously cooling to below-50 ℃, beginning to dropwise add a mixed solution of acetonitrile and tetrahydrofuran (10.0g/25ml), stirring for 5 minutes after dropwise addition, dropwise adding 17 beta-hydroxy-5, 9-androstadiene-3, 7-dione-3, 3-ethylidene ketal (the source: New Biomedicine Limited in Hunan, the purity is more than or equal to 99.30 percent, and the single impurity is less than 0.10 percent) tetrahydrofuran solution (38g/125ml), controlling the temperature to be between-50 ℃ and-90 ℃ after dropwise addition, reacting for 30 minutes, completely reacting, dropwise adding dilute hydrochloric acid to stop the reaction, layering, and concentrating the organic phase by pressure to a light yellow oily substance, wherein the weight is 40.5g, the yield is 106.5 percent, and the purity is 97.6 percent.
Step two: preparation of crude dienogest, 17 alpha-cyanomethyl-17 beta-hydroxy-4, 9-androstadien-3-one
Adding 410ml of acetonitrile into the reaction bottle in the first step, stirring for dissolving, adding 32.4ml of 50% fluoroboric acid water solution, controlling the temperature to be between 15 and 45 ℃, reacting for 2 to 4 hours, completely reacting, adjusting the pH to be between 7 and 8 by using 15% sodium carbonate solution, slowly pouring the reaction solution into 615ml of water, stirring for elutriation, filtering, drying a filter cake at the temperature of between 50 and 60 ℃ for 20 hours to obtain 33.8g of white-like solid, wherein the yield is 83.4%, the purity is 98.6%, and the maximum single impurity is a compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one (1.21%).
Step three: refining of dienogest
Adding 33.4g of crude dienogest into a reaction bottle, adding 396ml of 4-methyl-tetrahydropyran, adding 1.6g of medicinal activated carbon, heating to reflux and dissolve, carrying out hot filtration, collecting filtrate, concentrating the filtrate at 45 ℃ under reduced pressure to a small volume, cooling to 0-5 ℃ for crystallization for 2 hours, filtering, leaching a filter cake once by using cold 4-methyl-tetrahydropyran, drying the solid at 80 ℃ for 20 hours to obtain 26.5g of white crystalline particles, grinding or crushing the white crystalline particles into white powdery solid, wherein the yield is 80.3%, the purity is 99.5%, and the single impurity content is less than 0.10%. And (3) concentrating the mother liquor under reduced pressure to dryness to obtain a white powdery solid, wherein the purity of the white powdery solid is 93.8% by liquid phase detection, and the by-product, namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one: 5.8 percent and other impurities less than 0.1 percent.
Step four: recovery of dienogest from refined mother liquor
Putting the refined mother liquor into a single-neck flask, concentrating under reduced pressure until the refined mother liquor is dry, wherein the net weight is 8.5g, adding 160ml of acetonitrile, heating, stirring, dissolving, cooling to 10-25 ℃, adding 2.5ml of 70% perchloric acid aqueous solution, controlling the temperature to be 20-30 ℃, reacting for 30 min-1 h, concentrating under reduced pressure at 45-55 ℃, controlling the vacuum degree to be-0.07 Mpa to-0.05 Mpa, controlling the concentration time to be 50 min-70 min, slowly volatilizing the solvent, separating out a large amount of solid when half of the solvent is concentrated, stopping concentration, cooling to 20-30 ℃, continuing the reaction, and tracking the reaction liquor by HPLC until the by-product C is less than 1.0%. The reaction was stopped. Adjusting the pH value to 7-8 by using 15% sodium carbonate solution, slowly pouring the reaction solution into 180ml of water, stirring for elutriation, filtering, and drying a filter cake at 50-60 ℃ for 20 hours to obtain 6.8g of light yellow solid, wherein the yield is 80%, the purity is 98.2%, and the maximum impurity is compound C, namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one (0.89%).
Adding the light yellow solid into a single-neck flask, adding 70ml of 4-methyl-tetrahydropyran, adding 1.0g of medicinal activated carbon, heating to reflux and dissolve, carrying out heat filtration, collecting filtrate, concentrating at 45 ℃ under reduced pressure to a small volume, cooling to 0-5 ℃ for crystallization for 2 hours, filtering to obtain light yellow solid, and drying the solid at 70-80 ℃ for 20 hours to obtain 5.3g of light yellow crystalline particles, wherein the yield is 78%, the purity is 99.7%, and the content of single impurities is less than 0.10%.
Comparative example 1
Comparative example 1 is compared with example 1 except that the process uses an aqueous solution of perchloric acid instead of an aqueous solution of fluoroboric acid, and the rest is the same as example 1.
The product of the second step is a dark yellow solid, the yield is 80%, the purity is 97.5%, and the maximum single impurity is a compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one (1.8%).
Step four, light yellow solid (not the final light yellow crystal particles) is obtained, the yield is 70%, the purity is 96.3%, and the purity of the monohybrid (17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one) is 2.5%.
Comparative example 2
Comparative example 2 is compared with example 1 except that in step four, an aqueous solution of fluoroboric acid is used instead of an aqueous solution of perchloric acid, and the other steps are the same as in example 1.
Step four, light yellow solid (not the final light yellow crystal particles) is obtained, the yield is 71%, the purity is 96.9%, and the purity of the monohybrid (17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one) is 1.47%.
Claims (10)
1. A preparation method of dienogest is characterized in that 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal is dissolved, fluoboric acid is added, acidolysis is carried out to remove protection, and after complete reaction, treatment is carried out to obtain dienogest.
2. The process for producing dienogest according to claim 1, wherein the fluoroboric acid is present in the form of an aqueous solution of fluoroboric acid at a mass concentration of 40 to 50%.
3. The process for the preparation of dienogest according to claim 1, wherein the reaction temperature is 20-45 ℃.
4. A process for the preparation of dienogest according to any one of claims 1 to 3, characterized in that the solvent in which 17 α -cyanomethyl-17 β -hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylene ketal is dissolved is methanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, acetone or 4-methyl-tetrahydropyran.
5. The process for producing dienogest as claimed in claim 4, wherein the solvent in which 17 α -cyanomethyl-17 β -hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal is dissolved is acetonitrile.
6. A method for recovering dienogest from dienogest mother liquor, which is characterized in that dienogest obtained by the preparation method of any one of claims 1 to 5 is dissolved by a solvent to obtain dienogest mother liquor, perchloric acid or concentrated hydrochloric acid is added to react for a period of time, the temperature is raised to 45-55 ℃, reduced pressure concentration is carried out, partial solvent is concentrated until solid is separated out, the concentration is stopped, the temperature is reduced, the reaction is continued, and after the reaction is finished, the treatment is carried out to obtain dienogest.
7. The method as claimed in claim 6, wherein the solvent of the concentrated dienogest mother liquor is methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile.
8. The method as claimed in claim 6, wherein the perchloric acid is present in the form of an aqueous perchloric acid solution at a concentration of 70% by mass.
9. The method as set forth in claim 6, wherein the vacuum degree of the concentration under reduced pressure is from-0.07 MPa to-0.05 MPa.
10. The method according to any one of claims 6 to 9, wherein the dienogest is purified before the dienogest obtained by the production method according to any one of claims 1 to 5 is dissolved in a solvent, and the method for purifying dienogest comprises heating, refluxing and dissolving the dienogest in the solvent together with activated carbon to clear, filtering, and recrystallizing to obtain a refined dienogest.
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